Substance abuse and addiction represents a huge drain on North American society, in terms of economic and social costs, as well as the human individual cost. The need for effective medications to treat addiction is urgent. Although medications development has progressed for certain types of addiction, namely opioid addiction, these medications have significant drawbacks. There remain no currently approved therapies for many types of addiction such as methamphetamine or cocaine addiction. Further complicating matters is that many marginalized populations suffering from high levels of addiction also have very high levels of polydrug addiction that is, many individuals in these populations regularly use and are addicted to multiple substances. Treatment strategies for such individuals and populations are complex due to the various mechanisms underlying each type of addiction. Innovative strategies that target mechanisms common to different types of addiction may be of great benefit in treating such polydrug addictions, in addition to also be useful for treating single substance addictions. Researchers at The University of British Columbia have developed a promising lead compound as a potential addiction therapy. This peptide compound does not directly target drug receptors, but rather targets the association and learning mechanisms underlying addiction behaviors. These learning and association mechanisms have been shown to be critical for both the craving and the relapse aspects of addiction, and are not related to the reward aspects of drug use. It is a long range goal of the research project to conduct a human clinical trial using the lead peptide compound, with an initial target population of injection drug users where at least a portion of such drug users are addicted to multiple substances. Thus the short term goals proposed herein are to perform additional non-clinical experiments to position the project for a follow-on formal preclinical safety and toxicity program, in order to proceed quickly towards an FDA Investigational New Drug Application and/or Health Canada Clinical Trial Application. The experiments described in the research proposal include further testing of the lead compound in an animal model of polydrug addiction; determination of minimum efficacy dose, maximum tolerated dose, therapeutic index, and optimal dose of the lead compounds; full pharmacokinetic and biodistribution profiling of the lead compound in animal model; and investigation of an alternate mode of delivery, intranasal, to potential expand the applicability and feasibility of using the compound with a broader target population. PUBLIC HEALTH RELEVANCE: The proposed research project is intended to investigate and ultimately provide new medications for the treatment of addiction, in particular for the treatment of patients with multiple substance use disorders. For individuals in marginalized populations such as those found in many inner cities, and particularly in Vancouver's Downtown Eastside, addiction to multiple substances, such as heroin, cocaine, and/or alcohol, is widespread, and has devastating consequences both on the individual and on society. Drug addiction in such communities is very clearly a significant public health issue that requires new and innovative solutions, particularly in communities with high levels of polydrug use and addiction.